AB0134 RESTORATION OF ABERRANT GENE EXPRESSION OF MONOCYTES IN SYSTEMIC LUPUS ERYTHEMATOSUS VIA A COMBINED TRANSCRIPTOME-REVERSAL AND NETWORK-BASED DRUG REPURPOSING STRATEGY
Authors: D. Nikolakis, P. Garantziotis, G. Sentis, A. Fanouriakis, G. Bertsias, E. Frangou, D. Nikolopoulos, A. Banos, D. Boumpas
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Monocytes -key regulators of the innate immune response- are actively involved in the pathogenesis of systemic lupus erythematosus (SLE). Monocytes and macrophages constitute a major cellular compartment derived from hematopoietic myeloid precursors. Monocyte-macrophage lineage cells exhibit versatile immunoregulatory, inflammatory and tissue repairing capabilities and play an instrumental role in the development of systemic lupus erythematosus (SLE). Abnormal activation of autoreactive T and B cells in SLE could also be caused by dysregulated cytokine production by monocytes. Monocytes in SLE display excess production of the B-lymphocyte stimulator (BLyS) which promotes the survival and proliferation of B cells. <h3>Objectives</h3> We sought to identify novel compounds that might serve as monocyte-directed targeted therapies in SLE. <h3>Methods</h3> We performed mRNA sequencing in monocytes from 15 patients with active SLE and 10 healthy individuals. Disease activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Leveraging the drug repurposing platforms iLINCS, CLUE and L1000CDS<sup>[2]</sup>, we identified perturbagens capable of reversing the SLE monocyte signature. We identified transcription factors and microRNAs (miRNAs) that regulate the transcriptome of SLE monocytes, using the TRRUST and miRWalk databases, respectively. A gene regulatory network, integrating implicated transcription factors and miRNAs was constructed, and drugs targeting central components of the network were retrieved from the DGIDb database, in order to build a final drug-protein interaction network. <h3>Results</h3> Inhibitors of the NF-κB pathway, compounds targeting the heat shock protein 90 (HSP90), as well as a small molecule disrupting the Pim-1/NFATc1/NLRP3 signaling axis were predicted to efficiently counteract the aberrant monocyte gene signature in SLE. Based on our network-based drug repurposing approach, an IL-12/23 inhibitor, an EGFR inhibitor and the proteasome inhibitor bortezomib may represent potential drug candidates in SLE. <h3>Conclusion</h3> Application of two independent - a transcriptome-reversal and a network-based -drug repurposing strategies uncovered novel agents that might remedy transcriptional disturbances of monocytes in SLE. <h3>References</h3> [1]Ma W-T, Gao F, Gu K and Chen D-K (2019). The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review. Front. Immunol. 10:1140. doi: 10.3389/fimmu.2019.01140. [2]Li Y, Lee PY, Reeves WH. (2010). Monocyte and macrophage abnormalities in systemic lupus erythematosus. Arch Immunol Ther Exp (Warsz). 2010 Oct;58(5):355-64. doi: 10.1007/s00005-010-0093-y. Epub 2010 Jul 31. PMID: 20676786; PMCID: PMC3785254. [3]Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR. (1998). Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 41:1241–50. doi: 10.1002/1529-0131(199807)41:7&lt;1241::AID-ART15&gt;3.0.CO;2-H. [4]Kavai M, Szegedi G. (2007). Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus. Autoimmun Rev. (2007) 6:497–502. doi: 10.1016/j.autrev.2007.01.017. [5]Keenan AB, Jenkins SL, Jagodnik KM, et al. (2018). The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations. Cell Syst. 2018;6(1):13-24. doi:10.1016/j.cels.2017.11.001. [6]Lamb, Justin et al. (2006). The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science (New York, N.Y.) vol. 313,5795: 1929-35. doi:10.1126/science.1132939. [7]Csardi G, Nepusz T (2006). The igraph software package for complex network research. InterJournal, Complex Systems, 1695. https://igraph.org. <h3>Acknowledgements</h3> The authors Dimitrios Nikolakis and Panagiotis Garantziotis, contributed equally in this project and share main (first) authorship. <h3>Disclosure of Interests</h3> None Declared.